Effects of TrkB Activation on Abnormalities in Neocortical FS interneuron

TrkB 激活对新皮质 FS 中间神经元异常的影响

• 批准号: 10304051
• 负责人: David Allan Prince
• 金额: $ 3.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304051
• 关键词: Agonist; Anatomy; Animals; Applications Grants; Area; Award; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Cell Death; Cells; Chronic; Complement; Data; Development; Electrophysiology (science); Epilepsy; Epileptogenesis; Failure; Frequencies; Goals; Grant; In Vitro; Incidence; Inhibitory Synapse; Injury; Interneuron function; Interneurons; Light; Long-Term Effects; Maintenance; Measures; Modeling; Morphology; Mus; Neocortex; Nerve; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Output; Parvalbumins; Pharmacology; Physiological; Physiology; Presynaptic Terminals; Probability; Property; Prophylactic treatment; Reporting; Research; Research Training; Saline; Seizures; Slice; Somatostatin; Status Epilepticus; Structural defect; Structure; Synapses; Synaptic Transmission; Techniques; Testing; Training; Trauma; Tropomyosin; United States National Institutes of Health; base; brain abnormalities; career; confocal imaging; density; experience; experimental study; gamma-Aminobutyric Acid; gephyrin; hippocampal pyramidal neuron; immunocytochemistry; improved functioning; inhibitory neuron; mouse model; neocortical; nervous system disorder; neuronal cell body; novel strategies; parent grant; postsynaptic; prevent; preventable epilepsy; receptor; small molecule; synaptogenesis; transmission process

Project Summary Abnormalities in parvalbumin (PV) and somatostatin (SOM) interneurons are reported in a number of neurological disorders, including epilepsy. Therapy that improves function of defective interneurons is not available. Structural development and maintenance of interneurons is dependent on trophic support provided by brain derived neurotrophic factor activation of TrkB receptors (TrkB-Rs). In the undercut (UC) model of epileptogenic neocortical injury, chronic activation of TrkB-Rs with a selective small molecule partial agonist (LM22A-4, “LM” below) has long-term effects to reverse structural and functional abnormalities in inhibitory terminals of PV interneurons, enhance GABA release and increase the threshold for evoking epileptiform activity and seizures. The parent grant main goal is to determine whether these effects will be applicable to treatment or prevention of epilepsy in other models with different causes for seizures. The objective is to determine whether chronic treatment with a TrkB-Rs partial agonist, by increasing GABA release from nerve terminals of interneurons, or inducing new inhibitory synapse formation, will enhance inhibition in cortical networks and suppress epileptiform discharges. The specific aims of the parent grant include to: i) test the hypothesis that activation of TrkB-Rs with LM will reverse or prevent structural abnormalities in FS interneurons of UC cortex; ii) Examine effects of TrkB-Rs activation on functional properties of GABAergic inhibition in layer V; iii) Test the effects of LM on cortical network activity in UC animals. Proposed experiments include a) immunocytochemistry and confocal imaging to assess alterations in presynaptic terminals of interneurons; b) electrophysiological analysis of basic properties of inhibitory synaptic transmission from PV interneurons to pyramidal neurons of in vitro slices to detect effects of TrkB activation on unitary IPSCs, release probability and transmission failures. For this supplement grant we will study the effects of focal status epilepticus (FSE) on numbers, morphology and physiology of GABAergic interneurons in the cortical network and test possible mitigating effects of activation of TrkB-Rs with a small molecule partial agonist, PTXBD4-3 (BD). These results will complement and extend Aims 1, and 2 of the parent grant. Results of these experiments will provide information about mechanisms leading from interneuronal abnormalities to development of epilepsy and a potential approach to prophylaxis of epileptogenesis by enhancing trophic support of interneurons. Considering the frequency and untoward consequences of FSE, results may have potential translational importance.

项目摘要 据报道，白蛋白（PV）和生长抑素（SOM）中间神经元异常 神经系统疾病，包括癫痫。改善缺陷中间神经元功能的治疗不是 可用的。中间神经元的结构发展和维护取决于提供的营养支持 通过脑衍生的TRKB受体（TRKB-RS）的神经营养因子激活。在底切（UC）模型中 癫痫病新皮质损伤，具有选择性小分子的慢性激活TRKB-RS （下面的LM22A-4，“ LM”）具有逆转抑制性和功能异常的长期效应 PV中间神经元的末端，增强GABA释放并增加引起癫痫样的阈值 活动和癫痫发作。父母赠款的主要目标是确定这些效果是否适用于 在具有不同原因癫痫病因的其他模型中治疗或预防癫痫。目的是 通过增加Neve的GABA释放，确定使用TRKB-RS部分激动剂的慢性治疗是否 中间神经元的末端或诱导的新抑制突触形成，将增强皮质的抑制作用 网络并抑制癫痫样放电。父母赠款的具体目的包括：i）测试 假设用LM激活TRKB-RS将逆转或防止FS结构异常 UC Cortex的中间神经元； ii）检查TRKB-RS激活对GABA能功能特性的影响 V层的抑制作用； iii）测试LM对UC动物皮质网络活性的影响。提出的实验 包括a）免疫细胞化学和共聚焦成像，以评估突触前末端的改变 中间神经元； b）对PV抑制性突触传播的基本特性的电生理分析 在体外切片的锥体神经元中神经元，以检测TRKB激活对单一IPSC的影响， 释放概率和传输故障。对于此补充赠款，我们将研究焦点地位的影响 皮质网络中GABA能中间神经元的数量，形态和生理学数字，形态和生理学 并测试使用小分子部分激动剂PTXBD4-3激活TrkB-RS激活的可能作用 （BD）。这些结果将完成并扩展父母赠款的目标1和2。这些结果 实验将提供有关导致神经间异常的机制的信息 癫痫的发展和一种潜在的预防癫痫发生的方法，通过增强营养 支持中间神经元。考虑到FSE的频率和不良后果，结果可能具有 潜在的翻译重要性。